Organic Process Research & Development 2009, 13, 1068–1079
Full Papers
Removal of Heavy Metals from Organic Reaction Mixtures: Preparation and
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Application of Functionalized Resins
Damien Barbaras,†,‡ J o¨ rg Brozio, Ib Johannsen, and Thomas Allmendinger*
‡
§
,‡
NoVartis Pharma AG, Technical Research and DeVelopment, CH-4002 Basel, Switzerland, and UniVersity of Southern
Denmark, Department of Physics and Chemistry, DK-5230 Odense M, Denmark
6
Abstract:
described recently. Faced with similar problems during drug
development, we set up a toolbox of functionalized resins and
tested it on a number of heavy metal-contaminated products
and reaction mixtures.
Using a toolbox, sulfur and amine ligands are attached to a variety
of hydrophobic and hydrophilic resins, and the combinations were
tested for the removal of heavy metals from a number of products,
prepared by metal-catalyzed reactions. As a result, cheap combi-
nations of silica resins and simple polyamines proved to be among
the most effective metal scavengers particularly in apolar solvents
such as cyclohexane. Expensive cyclic polyamines are not suitable,
owing to kinetic retardation of complexation. Functionalized PEG-
based polymers, originally designed for solid phase synthesis, show
promising performance as metal scavengers. The results are
discussed and compared to alternative approaches for purification
such as salt-formation and chemical downstream transformation.
Choice and Preparation of Resins
The use of functionalized resins offers a simple suspension-
filtration sequence for the purification of metal-contaminated
product solutions. The design of such resins has some degree
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of freedom: (a) the nature of the solid support, (b) the linker or
spacer, (c) the complexing agent or ligand, and finally (d) the
loading of the resin. All of these factors may contribute to the
properties of the final resin. Thus, a toolbox or construction kit
was designed as shown in Table 1. We chose silica gel (S),
cross-linked polystyrene (P), and cross-linked polyethyleneg-
lycol (O) resins as support; the linkages to the ligands (a-n)
were made direct (1) or via methyl-, propyl-, and glycidox-
Introduction
Metal-organic chemistry is a cornerstone in synthesis. In
addition to the stoichiometric use of Mg and Li reagents, the
use of heavy metal catalysts is of utmost importance e.g. in
Heck and cross-coupling reactions whose application has
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ypropyl-spacers (2), (3), and (4), respectively.
For the preparation of silica-based resins, three approaches
were applied:
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reached industrial scale. The removal of toxic heavy metals
needs to be assured for drug substances at the ppm level which
has sometimes proved difficult. Several techniques to purge
product streams and effluents from metal contamination have
(
a) Activation of silica with thionyl chloride to give
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chloro-silica followed by nucleophilic substitution
(Table 2). Whereas polyamines react smoothly to
3,4
been already reviewed and have been divided into (1)
extraction and precipitation treatments and (2) solid phase
obtain the corresponding silica gels with useful
loading (S1f, S1g, and S1l, 0.4-1.0 mmol/g), sulfur
nucleophiles lead to resins S1b and S1e containing
less than 0.05 mmol/g of the ligand.
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treatments; a screening system for the latter method was
*
To whom correspondence should be addressed: Telephone: +41 (0)61 696
(b) Silanation of (3-bromopropyl)trimethoxysilane or (3-
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2 25. Fax: +41 (0)61 696 27 11. E-mail: thomas.allmendinger@novartis.com.
1
0
†
bromopropyl)trichlorosilane followed by nucleo-
philic substitution (Table 3).
Current address: Swiss Federal Institute of Technology (ETH) Z u¨ rich,
Laboratorium f u¨ r Organische Chemie, CH-8093 Z u¨ rich, Switzerland.
‡
Novartis Pharma AG.
University of Southern Denmark.
§
´
(
(
1) Part of D.B.’s master thesis at the Ecole Nationale Sup e´ rieure de
(6) Welch, C. J.; Albaneze-Walker, J.; Leonard, W. R.; Biba, M.; DaSilva,
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45. (b) Blaser, H. U.; Schmidt, E. Asymmetric Catalysis on Industrial
(7) The sometimes low solubility of aromatic compounds makes this
approach inefficient. For a recent successful alternative approach based
on the reslurry of the metal-contaminated compound in the presence
of soluble scavengers, see: Flahive, E. J.; Ewanicki, B. L.; Sach, N. W.;
O’Neill-Slawecki, S. A.; Stankovic, N. S.; Yu, S.; Guinness, S. M.;
Dunn, J. Org. Process. Res. DeV. 2008, 12, 637–645.
Scale: Challenges, Approaches and Solutions; Wiley-VCH Verlag
GmbH & Co. KGaA: Weinheim, Germany, 2004. (c) Schlummer, B.;
Scholz, U. AdV. Synth. Catal. 2004, 346, 1599–1626.
(
(
3) Garrett, C. E.; Prasad, K. AdV. Synth. Catal. 2004, 346, 889–900.
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Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2008.
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(8) For details, see the experimental section.
(
(9) (a) Firouzabadi, H.; Iranpoor, N.; Karimi, B.; Hazarkhani, H. Synlett
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11–314.
(10) Rosenberg, E. US 5.695.882, 1997.
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Vol. 13, No. 6, 2009 / Organic Process Research & Development
10.1021/op900102a CCC: $40.75 2009 American Chemical Society
Published on Web 10/20/2009